Youth suicide constitutes a major public health problem, ranking as the second leading cause of death for youth worldwide. Of all psychiatric disorders in youth, bipolar disorder imparts the greatest risk for suicide, followed by a substance use disorder. Mood disorder and substance use disorders commonly co-occur, and the combination increase the risk for completed suicide in adolescents exponentially over either disorder alone. Unfortunately, effective suicide prevention efforts, particularly for the ultra-high-risk population of youth with mood disorder and substance use, remain limited. This void in the treatment research may be understood by findings that a multitude of factors from a variety of domains contribute to suicidal risk;such factors remain too diffuse and multiply determined to be considered optimal targets for preventive interventions. Experts in the field have thus called for prospective, longitudinal studies in high-risk samples to systematically investigate specific mechanisms of suicide risk in adolescents. The American Association of Suicidology has specifically identified a need for research on proximal, dynamic and modifiable factors for substance use-to inform targeted preventive approaches for high-risk populations. PUBLIC HEALTH RELEVANCE: Youth suicide constitutes a major public health problem, ranking as the second leading cause of death for young people worldwide. Of all psychiatric disorders, bipolar disorder imparts the greatest risk for suicide, followed by a substance use disorder. Mood disorders and substance use disorders commonly co-occur, and the combination increases the risk for completed suicide in adolescents exponentially over either disorder alone. Improved understanding of the nature of these interrelated risk factors has the potential to inform targeted suicide prevention efforts for those at highest risk, thereby decreasing the morbidity, mortality and suffering associated with youth suicide.